| First Author | Nakamura Y | Year | 2024 |
| Journal | J Biol Chem | Volume | 300 |
| Issue | 7 | Pages | 107419 |
| PubMed ID | 38815862 | Mgi Jnum | J:352324 |
| Mgi Id | MGI:7702796 | Doi | 10.1016/j.jbc.2024.107419 |
| Citation | Nakamura Y, et al. (2024) Neuronal activity promotes secretory autophagy for the extracellular release of alpha-synuclein. J Biol Chem 300(7):107419 |
| abstractText | Extracellular secretion is an essential mechanism for alpha-synuclein (alpha-syn) proteostasis. Although it has been reported that neuronal activity affects alpha-syn secretion, the underlying mechanisms remain unclear. Here, we investigated the autophagic processes that regulate the physiological release of alpha-syn in mouse primary cortical neurons and SH-SY5Y cells. Stimulating neuronal activity with glutamate or depolarization with high KCl enhanced alpha-syn secretion. This glutamate-induced alpha-syn secretion was blocked by a mixture of NMDA receptor antagonist AP5 and AMPA receptor antagonist NBQX, as well as by cytosolic Ca(2+) chelator BAPTA-AM. Additionally, mTOR inhibitor rapamycin increased alpha-syn and p62/SQSTM1 (p62) secretion, and this effect of rapamycin was reduced in primary cortical neurons deficient in the autophagy regulator beclin 1 (derived from BECN1(+/-) mice). Glutamate-induced alpha-syn and p62 secretion was suppressed by the knockdown of ATG5, which is required for autophagosome formation. Glutamate increased LC3-II generation and decreased intracellular p62 levels, and the increase in LC3-II levels was blocked by BAPTA-AM. Moreover, glutamate promoted co-localization of alpha-syn with LC3-positive puncta, but not with LAMP1-positive structures in the neuronal somas. Glutamate-induced alpha-syn and p62 secretion were also reduced by the knockdown of RAB8A, which is required for autophagosome fusion with the plasma membrane. Collectively, these findings suggest that stimulating neuronal activity mediates autophagic alpha-syn secretion in a cytosolic Ca(2+)-dependent manner, and autophagosomes may participate in autophagic secretion by functioning as alpha-syn carriers. |
